Abstract

Human immunodeficiency virus (HIV)-positive women have a higher
prevalence of human papillomavirus (HPV) infection in the cervix
and anus, as well as squamous intraepithelial lesions (SILs) at
these sites, than do HIV-negative women matched for age and HIV
risk factors. Similarly, HIV-positive homosexual or bisexual men
have a higher prevalence of anal HPV infection and anal SIL than
do HIV-negative homosexual or bisexual men. In HIV-positive
individuals, the prevalence of HPV infection, the proportion
infected with multiple HPV types, and the prevalence of
anogenital SILs increase with decreasing CD4 count. This
situation may reflect loss of systemic immune response to HPV
antigens or local HPV-HIV interactions at the tissue or cellular
level. Despite the high levels of anogenital SILs, to date, there
has not been a significant increase in reported cases of invasive
anogenital cancer in HIV-positive individuals. However, several
years may be required for SIL to progress to invasive cancer, and
the advent of newer therapies for HIV that are expected to
prolong survival may paradoxically increase the risk of
progression to cancer in individuals with SILs if these lesions
do not regress spontaneously and remain untreated.

The association between human papillomavirus (HPV) and invasive
cervical cancer has been recognized for many years, initially
through the recognition that cervical cancer had the
characteristics of a sexually transmitted disease, i.e.,
association with number of sexual partners and the age at first
intercourse. In the last 10 years, with the advent of molecular
probes for HPV, a clear association between the presence of HPV
DNA in cervical cancer cells has been shown. Furthermore,
increasing understanding of the function of HPV proteins known to
be expressed in cervical cancer tissues, such as E6 and E7, has
established strong biologic plausibility for HPV as a key factor
in the pathogenesis of this disease.

Most of current understanding of the epidemiology of HPV
infection and anogenital neoplasia was derived from human
immunodeficiency virus (HIV)-negative study populations. In
recent years, it has become apparent that the prevalence of
anogenital HPV infection is higher among HIV-positive men and
women than in their HIV-negative counterparts. Likewise,
potentially precancerous lesions of the anogenital region are
more common among HIV-positive men and women. While this
increased prevalence has not yet led to a substantial increase in
the incidence of anogenital cancer in these populations, the
incidence of cancer may well increase as HIV-positive patients
live longer as a result of improvements in medical therapy for
HIV infection. The consequences of HPV infection may be a
paradigm for a possible shift in complications of HIV disease
from acute opportunistic infections to malignancies associated
with chronic viral infection. An understanding of HPV infection
and anogenital neoplasia in HIV-positive men and women is
therefore important, particularly since many, if not all, of the
HPV-associated anogenital cancers that occur in these patients
may be preventable.

The goals of this article are to summarize current understanding
of the role of HPV in the pathogenesis of anogenital neoplasia,
to describe current knowledge of the epidemiology of HPV
infection and anogenital neoplasia in HIV-positive men and women,
to describe HIV-HPV interactions that may play a role in
anogenital disease pathogenesis in HIV-positive individuals, and
to speculate on the effect of improved therapy for HIV infection
on the natural history of anogenital neoplasia.

Role of HPV in Pathogenesis of Anogenital Neoplasia

There are many different anogenital HPV types, and these are
generally divided into oncogenic and nononcogenic types by virtue
of the frequency of their association with invasive cervical
cancer. Of the oncogenic types, HPV type 16 is the most important
by virtue of its being the most common in cervical cancer,
followed by HPV types 18, 31, and 45 (1).
Many HPV types are also found, although with less frequency, in
some cases of cervical cancer; these include HPV types 33, 35,
39, 52, 56, 58, 59, and 68. Lastly, there is a large group of
nononcogenic types rarely if ever found by itself in cervical
cancer, and the ones that are most prominent in the genital
region are types 6, 11, 42, 43, and 44.

The mechanisms of oncogenicity of HPV are increasingly, but not
completely, understood. The HPV E6 protein binds and degrades its
cellular p53 protein target through a ubiquitin-mediated pathway,
whereas the HPV E7 protein inactivates the cellular RB protein,
as reviewed previously (2). Among their
many functions, p53 and RB shut down the cell cycle and
negatively regulate cell growth. The p53 protein also has been
shown to stimulate DNA repair enzymes after DNA damage,
presumably to limit the amount of chromosomal damage that occurs
in a cell (3,4). Consequently, through the
effects of E6 and E7, HPV infection may lead to genomic
instability in cells that continue to cycle despite the presence
of chromosomal damage (3,5). Consistent
with this hypothesis, chromosomal mutations as shown by studies
of loss of heterozygosity may be found in cervical cancer (6-8). The stage at which these changes
occur is not yet known, but one or more genetic changes may be
required for progression from high-grade squamous intraepithelial
lesion (HSIL) to cancer.

HPV on the cervix typically infects in the transformation zone,
where the squamous epithelium of the exocervix meets the columnar
epithelium of the endocervix. This squamocolumnar junction is a
relatively thin, highly metabolically active area of epithelium.
Most HPV infections occur here, and most HPV-related lesions,
including invasive cancer, arise from this area. A spectrum of
histopathologic abnormalities resulting from HPV infection has
been described. At the more benign end of the disease spectrum
are changes described as low-grade SILs (LSILs). The primary
features of LSILs include limited proliferation of basal or
parabasal cells with a high nuclear-to-cytoplasmic ratio and
koilocytosis (characterized by cells in the more differentiated
cell layers with an enlarged, irregular nucleus surrounded by a
clear area or halo). At the other end of the disease spectrum are
changes described as HSILs. The cardinal feature of HSILs is
marked proliferation of immature basal cells, which may replace
most or all of the normal epithelium, and mitoses in the more
superficial cell layers. The clinical importance of this grading
scheme is that almost all the invasive cancers arise from HSILs
and few, if any, arise from LSILs. Consistent with this
observation, almost all HSILs contain high- or medium-risk
oncogenic HPV types, whereas LSILs may contain a wider range of
types (9).

Epidemiologic studies of cervical HPV infection suggest that the
age-related prevalence of HPV infection as determined by
polymerase chain reaction (PCR) is highest among women in their
late teens and early twenties (10). These
data suggest that most women acquire HPV infection relatively
early after initiation of sexual activity. The age-related
prevalence of cervical HPV infection declines thereafter,
suggesting that immune mechanisms may either be clearing the HPV
infection or reducing it to levels that are undetectable with the
use of current technology. In addition, some of this age-related
decline may represent a cohort effect, given changes in sexual
behaviors that have occurred in the last few decades.

The age-related prevalence of cervical LSILs parallels that of
infection, but only a small proportion of women who acquire HPV
infection develop clinically detectable LSILs (10). An even smaller proportion of these women develop
HSILs or invasive cervical cancer. Currently, the rates in the
United States are approximately 8 per 100 000, and many of
these cancers are occurring in women who never have Pap smear
screening (11). In developing countries,
where there is no routine cervical cytology screening, the rates
are much higher, and cervical cancer constitutes a major cause of
mortality among young women.

Anal HPV Infection and Anal SILs

In the general population, anal cancer is more common among women
than among men. In the pre-HIV era, anal cancer was reported in
women approximately four times more often than in men, with an
incidence of 13 per 1 000 000 per year in the
United States (12). In the last 15 years,
the incidence of anal cancer has increased over 35% in
women (Hauser A: personal communication). In Denmark, rates of
anal cancer are lower than those in the United States; however,
between 1957 and 1987, the incidence of anal cancer among Danish
women more than tripled to 7.4 per 1 000 000 (13). Rates of anal cancer also rose among
Danish men during that time, increasing by 1.5-fold to 3.8 per
1 000 000.

The precise incidence of anal cancer among men with a history of
receptive anal intercourse has been difficult to determine
because cancer registries do not collect information on sexual
orientation or behavior. Men with a history of receptive anal
intercourse, however, may be at especially high risk of anal
cancer. Daling et al. (14) estimated that
the incidence of anal cancer among homosexual men was
approximately 35 per 100 000, rendering the incidence of
anal cancer in this group several times higher than current rates
of cervical cancer in women in the United States (11) and similar to rates of cervical cancer prior to
the introduction of routine cervical cytology screening.

Anal cancer shares many biologic properties with cervical cancer.
These cancers are similar histopathologically, and both are
strongly associated with HPV infection (15,16). The anal canal has a transformation zone, where
the columnar epithelium of the rectum joins the squamous
epithelium of the anus, which closely resembles that of the
cervix. Like the cervical transformation zone, the anorectal
junction is a common site of anal HPV infection and
HPV-associated SIL. The histology of anal SIL is similar to that
of cervical SIL, and anal HSIL is associated with the same HPV
types as cervical HSIL (15). Although
studies have never been done to determine if untreated anal HSIL
is the precursor to invasive anal cancer, this is likely to be
the case, based on knowledge of the natural history of cervical
HSIL. From a clinical standpoint, this is important because the
anorectal junction is about 2 cm inside the anal canal and thus
would not be visible with routine perianal inspection.

Anogenital HPV Infection and SILs in HIV-Positive Men and
Women

The data collected on the epidemiology and natural history of HPV
infection and SIL described above were derived from HIV-negative
individuals. There are several reasons to suspect that these data
may be different in HIV-positive men and women. First, both HIV
and HPV are sexually transmissible. Behaviors that increase the
risk of acquiring HIV infection may also increase the risk of
acquiring HPV infection and vice versa. Second, since the immune
response to HPV may play an important role in control of SIL, it
is possible that, as HIV-related immunosuppression increases,
immunity specific to HPV declines. Consequently, HIV-positive
individuals may be at higher risk of both acquiring HPV and
developing SIL related to HPV once HPV is acquired.

Clear patterns are emerging from studies of large numbers of
HIV-positive men and women. These patterns confirm the increased
risk of HPV infection and SIL in these groups. One of these
studies is a prospective cohort study known as the WIHS Study,
the Women's Interagency HIV Study. This ongoing study
enrolled 2015 HIV-positive women and 577 HIV-negative women who
were matched for age and HIV risk factors at six different cities
around the United States. HPV testing of a cervicovaginal lavage
specimen was performed on the women at baseline by use of PCR.
The procedure used was a modification of that employed by Ting et
al. (17) and used consensus primers from
the L1 region of the HPV genome, followed by specific typing for
39 different HPV types. Among these high-risk, HIV-negative
women, the prevalence of HPV was approximately 26%
(Palefsky JM: unpublished data), relatively high for their age
when compared with the data of Schiffman (10), which were collected in a population of women with
Kaiser Permanente medical insurance. However, the HIV-positive
women had even higher rates of prevalent HPV infection, and the
rates were highest among those with the lowest baseline CD4
count. Among women with CD4 levels less than 200/mm3 at baseline, approximately 70% had detectable HPV
infection (Palefsky JM: unpublished data). Independent risk
factors for cervical HPV infection at baseline included HIV
status, current smoker, younger age, and ethnicity (with
African-American women having the highest rates of HPV
infection).

Similar data have been obtained from a cohort study of 346
HIV-positive and 262 HIV-negative homosexual or bisexual men in
San Francisco. By use of a PCR HPV testing method similar to that
used for cervicovaginal lavage specimens in the WIHS study, anal
HPV infection was characterized in this study population at
baseline. Approximately 60% of the HIV-negative men had
anal HPV infection. Similar to our findings in the cervix, the
proportion of men with anal HPV infection was even higher among
the HIV-positive group and was highest among those with the
lowest CD4 levels. Among the HIV-positive men with CD4 counts
less than 500/mm3, HPV infection was nearly universal
(Palefsky JM: unpublished data). These data were similar to those
reported previously among homosexual men in Seattle (18).

Another interesting feature of HPV infection among both
HIV-positive women and men was the multiplicity of HPV types. Of
HIV-negative women in the WIHS study who were HPV-positive,
16% had more than one HPV type, compared with 42%
of HIV-positive women (Palefsky JM: unpublished data). Among
HIV-negative men, 23% had more than one type of HPV in the
anal canal, compared with 73% of HIV-positive men
(Palefsky JM: unpublished data).

With respect to cervical cytologic changes in the WIHS cohort at
baseline, a relatively high proportion of HIV-negative women had
abnormal cervical cytology (16%). Similar to the HPV data,
the proportion of HIV-positive women with abnormal cervical
cytology at baseline increased inversely with the baseline CD4
levels, and 53% of women with CD4 levels less than 200/mm3 had abnormal cytology (Fruchter R: personal
communication). Finally, among HIV-negative men in the San
Francisco cohort study, 21% had anal cytologic
abnormalities at baseline, while 72% of HIV-positive men
with CD4 counts less than 200/mm3 had abnormal anal
cytology (Palefsky JM: unpublished data). Taken together, these
findings indicate that HIV-positive women and men have a higher
prevalence of anogenital HPV infection, a higher number of HPV
types, and a higher rate of prevalent anogenital
lesions—each of these clearly associated with lower CD4
levels.

Relatively few data are currently available on the natural
history of HPV infection and SIL in these large study groups, and
these studies are in progress. However, some prospective data on
the projected incidence of anal HSILs are available from the San
Francisco men's cohort study. Men who entered the study
without HSIL were stratified according to HIV status and baseline
CD4 level. Among HIV-positive men who had CD4 levels less than
200/mm3 at baseline or between 200/mm3 and
500/mm3, the 4-year projected incidence of anal HSIL
was greater than 50% (Palefsky JM: unpublished data). Even
among those who entered the study with a CD4 level greater than
500/mm3, the projected incidence of HSILs was high
(approximately 30%). Finally, HIV-negative men in the
study had a projected 4-year incidence of 17%, putting
them potentially at the highest risk, since many of these men
will have a completely normal life span. These data indicate that
a high proportion of HIV-positive men, as well as a substantial
proportion of HIV-negative men, will develop HSILs if they are
followed for a sufficient period of time.

Invasive Anogenital Cancer in HIV-Positive Women and Men

The above data indicate a high prevalence and incidence of
anogenital HPV infection and putative precancerous anogenital
lesions. An important question that has emerged in the last few
years is whether these findings will translate into higher rates
of invasive anogenital cancer. Thus far, there has been no
significant increase in the rate of invasive cervical cancer
among HIV-positive women in the United States or in the
developing world (19). Data on anal cancer
are not as clear, since studies using different methods lead to
different conclusions. Rabkin and Yellin (19) did not find a significant increase in anal cancer
in single, never-married men in the San Francisco Bay Area in the
early 1990s when compared with the pre-HIV years. In contrast,
Melbye et al. (20) reported increased
relative risk of anal cancer compared with the general population
with increasing proximity to an AIDS diagnosis, implying a role
for increasing immunosuppression. However, these data should be
interpreted cautiously, since the results may be confounded by
the length of time that an individual may have been infected with
HPV. Overall, it seems likely that there has been some increase
(but not very large) in anal cancer, and the exact magnitude is
still unknown.

Based on knowledge of the natural history of cervical disease, it
seems likely that progression of HSIL to invasive cancer may
require several years. Until recently, most HIV-positive
individuals would have died of other HIV-related complications
before HSIL would have had the chance to progress, which may
explain why the high prevalence of anogenital HSIL in
HIV-positive women and men has not led thus far to a dramatically
large increase in cervical or anal cancer.

Despite the absence of a clear increase in cervical cancer in
HIV-positive women, it is important to recognize that, once it
develops, cervical cancer may be very aggressive in HIV-positive
women, and extreme vigilance on the part of the clinician is very
important (21,22). Conversely, cervical
cancer may be an indicator of HIV infection, particularly in
those regions with the highest HIV prevalence, and women with
cervical SIL or cervical cancer should be strongly considered for
HIV testing.

In the case of cervical disease, the clinical implications of
these findings are that aggressive screening, treatment, and
follow-up for cervical SIL are necessary. In the case of anal
disease, the data indicating the need for an anal-screening
program modeled on that used for cervical disease are compelling.
Studies have been performed recently that validate the use of
anal colposcopy as a diagnostic tool (23)
and anal cytology as a screening tool (24). Barriers to implementation of such a screening program include
the paucity of studies showing that anal HSIL progresses to
invasive cancer and that a screening program would have an impact
on the rate of anal cancer. However, such studies are very
unlikely to be performed, given the ethical issues of following
an individual without treatment once HSIL is diagnosed. Other
barriers include the absence of widespread expertise in the
performance of anal diagnostic techniques and the morbidity
associated with most treatments for anal lesions. Were such a
screening program to be implemented in the future, individuals
most likely to benefit would include HIV-positive and
HIV-negative men with a history of receptive anal intercourse.
Because of data showing that women with cervical HSIL or vulvar
cancer have a high prevalence of anal SIL and anal cancer (25,26), HIV-positive and HIV-negative
women with high-grade cervical or vulvar lesions should also be
considered for screening. Data on anal HPV infection and anal SIL
in HIV-positive women without cervical disease are still
emerging, but several earlier studies (27,28) have shown that, similar to cervical HPV infection
and cervical SIL, the prevalence of anal lesions is highest among
HIV-positive women with the lowest CD4 levels.

Mechanisms of HIV-HPV Interaction

Several mechanisms of interaction between HIV and HPV may play a
role in the higher prevalence and incidence of anogenital SIL in
HIV-positive women and men. One such mechanism is the systemic
immune response to HPV. It is known that women who have
iatrogenic immunosuppression secondary to organ transplantation
are at increased risk of developing cervical and vulvar cancers
when compared with age-matched women with normal immunity (29). Recently, one study (30) showed that a smaller proportion of women with HPV
type 16 infection and cervical SIL have cytotoxic T-cell
responses to the HPV type 16 E6 and E7 proteins than women who
were HPV type 16 positive without cervical disease. Other studies
of T-cell proliferative responses (31,32)
also confirm that HPV-positive women without disease have higher
response rates than women with lesions. These data suggest that,
once a woman acquires HPV infection, having a cell-mediated
immunity (CMI) response is associated with protection against
lesion development. Conversely, if HIV infection leads to global
impairment of CMI responses, including those to HPV antigens,
then loss of that CMI response to HPV antigens may be important
in the pathogenesis of anogenital disease and may explain in part
the higher levels of HPV infection and SIL among those
HIV-positive individuals with the lowest CD4 levels.

Local interactions at the tissue and cellular levels between HIV
and HPV may also play a role in potentiation of anogenital
neoplasia in HIV-positive individuals (Fig. 1). Although the viruses are likely to be found in
different cell types (33) (HPV in the
epithelium and HIV in local Langerhans' cells and stromal
cells), one possibility for interaction between these two viruses
locally is through production of HIV-1 tat, which has been shown
to be secreted by HIV-infected cells and may be able to
up-regulate expression of the HPV type 16 E6 and E7 genes (34). Aberrant cytokine expression by
HIV-infected cells may also play a role in potentiating HPV
infection. Perhaps most controversial is the possibility of
co-infection with HPV and HIV in the same epithelial cell and the
possibility of mutual transactivation between the viruses.

Taken together, these disparate observations may be used to
construct a model for the interplay between HPV and HIV in the
pathogenesis of anogenital SIL and cancer (Fig. 2). In this model, individuals acquire HPV infection
relatively early on after initiation of sexual activity and, in
many cases, before HIV infection. HIV is acquired at one or more
moments in time, and these individuals may continue to acquire
different strains of HPV as well. As long as the systemic and
local immune responses remain intact, HPV replication and gene
expression are controlled and there are no anogenital lesions. If
HIV infection is allowed to persist and the immune response
deteriorates, higher levels of viral replication and expression
of HPV-transforming genes may lead to development of a low-grade
lesion. With time, which may vary considerably from one
individual to another, the disease may progress to HSIL. As
described earlier, the high prevalence of HSIL does not appear to
be accompanied by increases in the rate of anogenital cancer
because of HIV-related mortality before progression of HSIL to
cancer occurs.

Conclusions: What Does the Future Hold?

The natural history of anogenital HPV infection and SIL in the
era of highly active antiretroviral therapy (HAART) may represent
a paradigm for HIV-related complications of the future. HAART has
been shown to dramatically reduce systemic HIV viral load and to
reduce the incidence of some opportunistic infections. Because
HAART has not been in use for an extended period of time, it is
not yet clear how much it will prolong the survival of
individuals with HIV infection. Two scenarios are possible (Fig.
3). If individuals go on HAART after
developing HSIL and if partial or complete restoration of immune
response to HPV occurs, then one might expect HPV levels to
decrease and HSIL to regress. If that is the case, then a
decreased incidence of anogenital cancer from current levels
would be expected. Conversely, if HAART permits individuals to
live longer but does not have a significant impact on the immune
response to HPV, then the disease in individuals with HSIL might
now have the time to progress to invasive cancer, resulting in an
increased incidence of anogenital cancer. It is not yet clear
which of these two scenarios is correct. However, the most that
HAART therapy could be expected to achieve would be to restore
the immune system of an HIV-positive individual to one as
functional as that of an HIV-negative individual. Since most
HSILs do not regress spontaneously, even in HIV-negative
individuals, the second scenario seems more likely at this time.
Clearly, further natural history studies of men and women on
HAART are needed, as are studies of the interactions between HIV
and HPV in the pathogenesis of anogenital cancer.

Schematic representation of possible interactions between human
immunodeficiency virus (HIV) and human papillomavirus (HPV) at
the tissue and cellular levels in the pathogenesis of anogenital
squamous intraepithelial lesions and invasive anogenital cancer.
HPV infection is restricted to the epithelium, as shown in the
shaded cells. HIV infection, as shown in the striped cells, is
located primarily in stromal cells (1) such as circulating
T cells and possibly fibroblasts or other stromal elements or
Langerhans' cells within the epithelium (2). HIV and
HPV co-infection in the same epithelial cells (3) (dotted
cells) is also a theoretical possibility. Possible interactions
include secretion of HIV-1 tat by Langerhans' or stromal
cells which may up-regulate HPV gene expression or other factors
such as cytokines. Cells infected with both viruses may also
transactivate each other.

Schematic representation of possible interactions between human
immunodeficiency virus (HIV) and human papillomavirus (HPV) at
the tissue and cellular levels in the pathogenesis of anogenital
squamous intraepithelial lesions and invasive anogenital cancer.
HPV infection is restricted to the epithelium, as shown in the
shaded cells. HIV infection, as shown in the striped cells, is
located primarily in stromal cells (1) such as circulating
T cells and possibly fibroblasts or other stromal elements or
Langerhans' cells within the epithelium (2). HIV and
HPV co-infection in the same epithelial cells (3) (dotted
cells) is also a theoretical possibility. Possible interactions
include secretion of HIV-1 tat by Langerhans' or stromal
cells which may up-regulate HPV gene expression or other factors
such as cytokines. Cells infected with both viruses may also
transactivate each other.

Model for the role of systemic immune response in the
pathogenesis of anogenital squamous intraepithelial lesions
(SILs) and invasive anogenital cancer. Human papillomavirus (HPV)
infection is acquired early after initiation of sexual activity,
followed thereafter by human immunodeficiency virus (HIV)
acquisition. Additional HPV types, represented by different
lines, may be acquired with new exposures. Early in the natural
history of HIV infection, systemic immune responses remain
relatively intact. HPV replication levels remain low, and there
are no anogenital lesions. With advancing HIV disease, systemic
immunity is attenuated, and loss of control of HIV replication is
seen as depicted by increased HPV levels. This is accompanied by
development of low-grade SIL (LSIL), which may progress over time
to high-grade SIL (HSIL) if the lesion remains untreated and the
HIV disease continues to progress. In most individuals,
progression of HSIL to invasive cancer does not occur because
they die of other HIV-related complications first. N =
normal.

Model for the role of systemic immune response in the
pathogenesis of anogenital squamous intraepithelial lesions
(SILs) and invasive anogenital cancer. Human papillomavirus (HPV)
infection is acquired early after initiation of sexual activity,
followed thereafter by human immunodeficiency virus (HIV)
acquisition. Additional HPV types, represented by different
lines, may be acquired with new exposures. Early in the natural
history of HIV infection, systemic immune responses remain
relatively intact. HPV replication levels remain low, and there
are no anogenital lesions. With advancing HIV disease, systemic
immunity is attenuated, and loss of control of HIV replication is
seen as depicted by increased HPV levels. This is accompanied by
development of low-grade SIL (LSIL), which may progress over time
to high-grade SIL (HSIL) if the lesion remains untreated and the
HIV disease continues to progress. In most individuals,
progression of HSIL to invasive cancer does not occur because
they die of other HIV-related complications first. N =
normal.

Model for the role of systemic immune response in the
pathogenesis of anogenital squamous intraepithelial lesions
(SILs) and invasive anogenital cancer in the era of highly active
antiretroviral therapy (HAART). HSIL = high-grade SIL;
LSIL = low-grade SIL. Upper panel: If HAART therapy
results in both restoration of systemic immune responses,
including those to human papillomavirus (HPV) antigens, and
prolongation of life, then individuals with HSIL may have
decreased levels of HPV and regression of HSIL. The net result
would be a rate of invasive anogenital cancer that parallels that
of human immunodeficiency virus-negative individuals. Lower
panel: If HAART leads to prolongation of life but does not
fully restore immunity to HPV, then no regression of HSIL will be
seen. In this case, the prolongation of life may increase the
risk of progression to invasive cancer, since there may now be
sufficient time for progression before the individual dies of
other causes. N = normal.

Model for the role of systemic immune response in the
pathogenesis of anogenital squamous intraepithelial lesions
(SILs) and invasive anogenital cancer in the era of highly active
antiretroviral therapy (HAART). HSIL = high-grade SIL;
LSIL = low-grade SIL. Upper panel: If HAART therapy
results in both restoration of systemic immune responses,
including those to human papillomavirus (HPV) antigens, and
prolongation of life, then individuals with HSIL may have
decreased levels of HPV and regression of HSIL. The net result
would be a rate of invasive anogenital cancer that parallels that
of human immunodeficiency virus-negative individuals. Lower
panel: If HAART leads to prolongation of life but does not
fully restore immunity to HPV, then no regression of HSIL will be
seen. In this case, the prolongation of life may increase the
risk of progression to invasive cancer, since there may now be
sufficient time for progression before the individual dies of
other causes. N = normal.

Supported by Public Health Service (PHS) grants CA54053 and
CA63933 from the National Cancer Institute, National Institutes
of Health (NIH), Department of Health and Human Services, as well
as by PHS grant AI-DE34989 from the National Institute of Allergy
and Infectious Diseases and the National Institute of Dental
Research, NIH.

We acknowledge the subjects and investigators of the University
of California, San Francisco, Anal Cancer Study and the
Women's Interagency HIV Study.